P854: EFFECT OF HPSE AND HPSE2 SNPS ON THE RISK OF DEVELOPING PRIMARY PARASKELETAL MULTIPLE MYELOMA
Authors: Olga Ostrovsky, Katia Beider, Hila Magen, Merav Leiba, Israel Vlodavsky, Arnon Nagler
Journal: HemaSphere (2023)

Topic: 13. Myeloma and other monoclonal gammopathies - Biology & Translational Research Background: Extramedullary multiple myeloma (EMM) is subtype of multiple myeloma (MM) that involves the presence of myeloma cells outside the bone marrow. The pathogenesis of bone-related EMM is not fully understood. Stromal cell-derived factor 1 (SDF-1), CXCR-4 chemokine receptor, inflammatory cytokines, immune cell adhesion molecules have been shown to be involved. Heparanase (HPSE), the sole heparan sulfate (HS) degrading endoglycosidase, plays an important role in supporting and promoting myeloma progression, maintenance of plasma cell stemness, and resistance to chemotherapy. The HPSE2 gene encodes a close heparanase homolog, named heparanase-2 (Hpa2). It binds strongly to HS, inhibits heparanase enzymatic activity, and appears to function as a tumor suppressor. The role of heparanase-2 in multiple myeloma has not been elucidated. Aims: The aim of the present study was to explore the role of HPSE and HPSE2 functional single nucleotide polymorphisms (SNPs) in MM. Methods: The retrospective study included 278 multiple myeloma patients (174 males and 104 females) and 211 controls. Fifty patients with primary EMM were identified. Forty-one were diagnosed with paraskeletal disease (PS), one with EMM from hematogenous spread and two had both bone-depended and bone-independent EMM. One patient was diagnosed with solitary plasmacytoma, and five developed plasma cell leukemia. In the present study, 5 previously studied functional SNPs of the HPSE gene and 11 novel SNPs of the HPSE2 gene were examined. Results: A very significant association between two enhancer (rs4693608 and rs4693084), and two insulator (rs4364254 and rs4426765) HPSE SNPs and primary bone-related EMM was observed (Figure-I). In our previous studies, we investigated the interaction between rs4693608 and rs4364254. We allocated all possible HPSE genotype combinations into three groups (HR, MR, and LR) correlating with high, intermediate and low heparanase mRNA expression levels. Correlations were analyzed in HR (genotypes AA-TT and AA-TC), MR (genotypes AG-TT and AG-TC), and LR (genotypes GG-TT, GG-TC, GG-CC and AG-CC) groups. Frequency of the LR genotype was significantly higher in patients with bone-related EMM (44%) compared with patients without EMM (16.1%), χ2=16.036, p=0.00033 after Yates’ correction (Figure-I). SNP rs657442, located in intron 9 of the HPSE2 gene, revealed a significant protective association with primary paraskeletal disease and lytic bone lesions. In addition, patients with genotypes AA-AA and AG-AC (rs4693608-rs4426765) had an increased risk of being diagnosed at stage II and III of the disease. The impact of rs658225 and rs754585 HPSE2 gene SNPs was noted in secondary EMM. Summary/Conclusion: The present study demonstrates a promoting (HPSE gene) and protective (HPSE2 gene) role of regulatory elements in the development of bone-related EMM and bone morbidity, and suggests that an increase in heparanase-2 expression can lead to effective suppression of heparanase activity in multiple myeloma accompanied by extramedullary disease and osteolytic bone disease. The effect of signal discrepancy between myeloma cells and normal cells of the tumor microenvironment is proposed as a mechanism for the involvement of heparanase in primary PS (Figure-II).Keywords: SNP, Multiple myeloma